The overall goal of this proposal is to further our understanding of the development and function of splenic B cells. The splenic B cell population can be divided into the marginal zone (MZ) and follicular (FO) B cell subsets based on anatomical location, cellular surface molecules, and functional immune responses. We are particularly interested in the development of the MZ B cell population, the role it plays in antibody responses, and the receptors that positively or negatively regulate cellular activity. A large expansion of MZ B cells occurs in nearly all established mouse models of autoimmune disease before any signs of pathological autoimmunity are observed. The significance of this phenomenon and its role in the autoimmune disease process has, surprisingly, been poorly investigated. Additionally, the mechanisms governing the activation and regulation of the MZ B cells following a bacterial challenge are not fully understood. Using a variety of cellular and molecular techniques, we propose to test the hypothesis that MZ B cells play an immunoregulatory role via IL-10 secretion in response to a blood-borne bacterial challenge. The findings will provide a better understanding of the mechanism by which MZ B cells respond during a bacterial infection and identify potential targets for therapeutic intervention. The following specific aims are designed to test our hypothesis: Aim 1: Determine if MZ B cells secrete IL-10 in response to a blood-borne bacterial challenge. Working Hypothesis: Antigen-specific MZ B cells secrete IL-10 in response to S. pneumoniae challenge. Aim 2: Determine the role of MZ B cell IL-10 production during response to a blood-borne bacterial challenge. Working Hypothesis: Antigen-specific MZ B cells play an immunoregulatory role via IL-10 secretion following S. pneumoniae challenge. Aim 3: Determine the mechanism by which B cells are activated to secrete IL-10. Working Hypothesis: B cells secrete IL-10 following gram+ and gram- bacterial challenge. RELAVANCE TO PUBLIC HEALTH: The goal of this project is to understand how the immune system fights off invading bacteria and affords protection from becoming sick. Once we understand how the immune system works, we will be able to develop new drugs and vaccination strategies to combat bacterial infections.